Field of the Invention
This invention relates generally to stable liquid formulations of volatile gas anesthetics. More in particular, the present invention comprises stable liquid nanoemulsions of volatile gas anesthetics, as well as methods of preparation, testing, and administration, such as, via injection.
Description of the Related Art
Volatile gas anesthetics include, among other compounds, a family of halogenated ethers that are highly hydrophobic liquids at room temperature, wherein the anesthetic potency is directly proportional to the lipid solubility of the volatile gas anesthetic. When exposed to ambient air, volatile gas anesthetics quickly evaporate depending on their temperature or latent heat of vaporization. The most commonly used volatile gas anesthetics at the present time are isoflurane, sevoflurane, and desflurane.
Currently, the only method of delivery, i.e., uptake and distribution, of vaporized volatile gas anesthetics is via inhalation into the lungs of a patient via a closed or open breathing circuit consisting of plastic tubing, face mask, laryngeal mask airway or endrotracheal tube, producing induction and maintenance of an artificial, reversible state of unconsciousness or general anesthesia. The delivery of one or more volatile gas anesthetics via inhalation is currently widely used, however, this requires the use of expensive and specialized equipment and instrumentation to vaporize the volatile gas anesthetic, which is supplied in a liquid state, and to mix or dilute with other gases, such as, oxygen or compressed air, in order to yield therapeutic, but non-toxic concentrations of anesthetic(s). Instruments to detect and analyze concentrations of the anesthetic(s) in exhaled gas, such as infrared gas analyzers, are also used in conjunction with inhalation anesthesia.
Surgery requires anesthetic agents that can induce analgesia, anesthesia, and amnesia and muscle relaxation. Volatile gas anesthetics are complete anesthetics, that is, at low concentrations they provide sedation, amnesia and analgesia, while at higher concentrations they also induce unconsciousness or general anesthesia and muscle relaxation. Conventional intravenous anesthesia induction agents such as dexmedetomidine (precedex), ketamine, propofol, thiopental or etomidate (amidate) are hypno-sedatives or major tranquilizers that are used for sedation, amnesia or general anesthesia, but are not complete anesthetics because they do not have sufficient analgesic or muscle relaxation properties (Eger II, 2004).
Therefore, in order to achieve an acceptable state of anesthesia for surgery, the present state of the art involves the administration of combinations of intravenous agents, potent narcotic analgesics, neuromuscular relaxants, as well as inhaled volatile gas anesthetics, by trained anesthesiologists and anesthetists, in order to achieve all of the desired and/or required physiologic effects. Generally, intravenous agents are used to induce sleep, and then inhaled volatile gas anesthetics are provided to maintain the state of general anesthesia. Neuromuscular blocking agents are also used to potentiate muscle relaxation. Although induction and maintenance of general anesthesia can be done solely with some volatile gas anesthetics, induction of anesthesia via inhalation of volatile gas anesthetics is unpleasant and can irritate the patient's airway while a patient is awake.
Thus, a number of benefits may be realized from stable liquid formulations of volatile gas anesthetics including but not limited to eliminating the need for inhalation of volatile gas anesthetics via the patient's airway, as well as rendering the administration of numerous agents in order to induce and/or maintain a desired state of anesthesia in a patient unnecessary.
One method of preparation of stable liquid formulations of volatile gas anesthetics in fluoropolymer-based emulsions is disclosed in U.S. Patent Application Publication No. 2008/0234389, FLUOROPOLYMER-BASED EMULSIONS FOR THE INTRAVENOUS DELIVERY OF FLUORINATED VOLATILE ANESTHETICS by Mecozzi et al. Specifically, Mecozzi et al. discloses emulsions and nanoemulsions of perfluorinated and/or perhalogenated volatile anesthetics, for intravenous delivery to a patient to induce and maintain anesthesia in a patient. (Mecozzi et al., paragraph [0012]). To accomplish the same, Mecozzi et al. discloses that “the present formulations comprise a combination of a surfactant, such as one or more semi-fluorinated block copolymers, and a stabilizing additive, such as one or more perhalogenated fluorocarbons, capable of generating an emulsion of a large amount of a fluorinated volatile anesthetic dispersed in an aqueous solution.” (Mecozzi et al., paragraph [0013]). Mecozzi et al. further state that “the present therapeutic formulations provide enhanced delivery performance relative to conventional lipid-base delivery systems by enabling emulsions having higher concentrations of fluorinated volatile anesthetics.” (Mecozzi et al., paragraph [0014]). Further, with respect to the formulations akin to at least some embodiments of the present invention, Mecozzi et al. state that “combinations of simple lipids such as soy bean oil and glycerol (Intralipid) could be used for making anesthetic emulsions. While these results demonstrate the potential feasibility of lipid emulsions for the delivery of volatile anesthetics, there are significant drawbacks to this approach which hinder its practical implementation. First, emulsions of volatile fluorinated anesthetics based on Intralipid are not expected to be stable over time at high anesthetic concentrations. The effectiveness of these formulations for intravenous administration of volatile anesthetics, therefore, is expected to degrade significantly as a function of time. This property is undesirable as it renders such lipid-based formulations short practical lifetimes and shelf lives. Second, common lipids such as Intralipid have been shown to emulsify a maximum of 3.6% in volume of sevoflurane. This substantial limitation on the volume of anesthetic capable of emulsification is expected to present a significant challenge for practical implementation of lipid-based delivery systems for intravenously administered fluorinated volatile anesthetics.” (Mecozzi et al., paragraph [0009]).
It was subsequently determined, however, that a fluoropolymer-based sevoflurane emulsion, such as is disclosed by Mecozzi et al., produced an unexpected allergic-type clinical reaction in canines (Johnson et al., 2011). In an abstract co-authored by Mecozzi, it states that although the fluorocarbon-based sevoflurane emulsion produced general anesthesia in dogs, the dogs also experienced hypotension and clinical signs of an allergic-like response, i.e., vasodilation, urticaria, and pruritus upon recovery (Johnson et al., 2011). It was further determined that emulsions lacking sevoflurane, while failing to induce anesthesia, still elicited the allergic response (Johnson et al., 2011). The conclusion of the study was that an allergic response leading to histamine release, likely initiated by the fluorocarbon-based polymer F13M5 of the emulsion associated with intravenous fluorocarbon-based emulsion of sevoflurane, via an immunoglobulin pathway, and therefore, the usefulness of the formulation was deemed limited (Johnson et al., 2011). It is believed that the incorporation of a perfluorinated stabilizing additive in combination with the fluorocarbon-based polymer F13M5, further exacerbated the allergic response observed in the canine subjects.
Thus, it would be highly beneficial to provide stable liquid formulations of volatile gas anesthetic in a medium that does not induce undesirable responses or side effects upon administration of the formulation to a patient.